Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.

Although overt hyperglycaemia does not develop until ?-cell failure develops, insulin resistance is a main feature of type 2 diabetes. The term insulin resistance identifies the inability of insulin to exert a normal biological action at the level of its target tissues. Though insulin exerts a variety of effects, in the current clinical use, insulin resistance refers to the inability of circulating insulin to promote glucose utilisation in the skeletal muscle and adipose tissue, and to properly suppress endogenous glucose production (mainly in the liver). As such insulin resistance not only characterises type 2 diabetes [1DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev, 1997, 5, 177-269.

Click here to see the Library]but it is very common in pre-diabetic patients [2Tripathy D, Carlsson M, Almgren P, et al. Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes, 2000, 49, 975-80.

Click here to see the Library]as well as in individuals with central obesity, dyslipidaemia, hypertension, endothelial dysfunction, hyperuricemia, and microalbuminuria [3Reaven GM. Insulin resistance: a chicken that has come to roost. Ann NY Acad Sci, 1999, 18, 45-57.

Click here to see the Library], while more recent epidemiological studies have indicated that insulin resistance may be an independent risk factor for cardiovascular mortality both in the general [5Goff DC Jr, Zaccaro DJ, Haffner SM, Saad MF. Insulin Resistance Atherosclerosis Study. Insulin sensitivity and the risk of incident hypertension: insights from the Insulin Resistance Atherosclerosis Study. Diabetes Care, 2003, 26, 805-9.

Click here to see the Library]population. Therefore, the comprehension of the mechanisms responsible for impaired insulin action is fundamental in the attempt to ameliorate insulin resistance and to account for the favourable effects of insulin sensitisers. Among these compounds, metformin has the largest clinical use. Employed for almost 50 years in Europe, it has been more recently introduced in the United States. The drug exerts an antihyperglycaemic effect, with minimal risk of hypoglycaemia. The initial observation that metformin reduces plasma glucose levels without increasing, and sometime decreasing circulating insulin levels, has indicated that the drug improves insulin sensitivity. Because of the effect on insulin sensitivity and the low risk of hypoglycaemia, metformin has been recently used for prevention of type 2 diabetes [7Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346, 393-403.

Click here to see the Library]. In order to appreciate this insulin sensitising effect, a brief discussion of the pathophysiology and cellular mechanisms of insulin resistance in diabetes and associated conditions is indicated.

Click here to see the Library]. The concomitance of increased endogenous glucose production and high plasma insulin levels provide direct evidence for the liver insulin resistance. Accelerated gluconeogenesis is the major determinant of the excessive glucose release from the liver in diabetic individuals [12Gastaldelli A, Baldi S, Pettiti M, et al. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes, 2000, 49, 1367-73.

Click here to see the Library]. It is conceivable, in these patients, that reduced glucose oxidation and concomitant increase of anaerobic glycolysis in peripheral tissue could ensure an excessive supply of 3-carbon atom compounds to the liver. Therefore, insulin resistance in peripheral tissues and liver may result in a vicious cycle resulting in progressive increase in fasting plasma glucose levels.

Click here to see the Library]. Excessive FFA release is also supported by the lack of the inhibitory effect of insulin on hormone-dependent lipase. Increased FFA availability can worsen hepatic and peripheral insulin resistance [17Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest, 2002, 32 (suppl. 3), 14-23.

Click here to see the Library]and favour VLDL-triglyceride synthesis and release from the liver. Ectopic accumulation of fat in the liver and muscle [18Yki-Jarvinen H. Ectopic fat accumulation: an important cause of insulin resistance in humans. J Roy Soc Med, 2002, 95 (suppl. 42), 39-45.

Click here to see the Library]correlates with the degree of insulin resistance and it is believed to contribute drastically to the impairment of insulin action.

Insulin-mediated glucose utilisation and metabolism is the final result of the activation of a complex cascade of events involved in the insulin signalling process [20Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia, 2002, 45, 1475-83.

Click here to see the Library]. Alteration of one or more of these events can result in impaired insulin action. Though complex, three main steps are likely to be involved in the generation of insulin resistance: 1) insulin binding to the cell membrane receptor, 2) insulin receptor phosphorylation, and 3) intracellular insulin signalling.

The insulin receptor is a heterotetrameric protein consisting of two ?-subunits in the extracellular domain and two ß-subunits with main intracellular domain. Upon insulin binding of the ?-subunits, the intrinsic kinase activity in the ß-subunits is activated leading to phosphorylation of the adjacent ß-subunit. The autophosphorylation of the insulin receptor allows the activation of insulin receptor substrate (IRS-1, -2, -3, -4) protein family. These proteins exert an important regulatory action on other mediators like phospho-inositol-3-kinase (PI3-kinase). The contribution of IRS-1 and -2 to insulin resistance has been recently demonstrated with knock-out genetic experiments. These studies proved that IRS-2 can play a vicariate role in absence of IRS-1, while IRS-2 knock-out results in impaired insulin action as well as insulin secretion [21Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol, 2002, 57, 1-9.

Click here to see the Library]. Activation of PI3-kinase catalyses the formation of PI-3,4,5-phosphate allowing the activation of PKB/AKT and phosphatidilinositol-3,4,5-phosphate kinase-1 (PDK-1). The phosphorylation of PKB/AKT regulates the kinase cascade involved in the insulin signal transduction responsible for GLUT-4 translocation from the intracellular membrane compartment to the cell membrane allowing active transmembrane glucose transport and phosphorylation, activation of the glycolytic flux, as well as glycogen and protein synthesis. Moreover, PDK-1 determines the phosphorylation and activation of atypical protein kinase ?/?, also modulating GLUT-4 translocation [20Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia, 2002, 45, 1475-83.

Given the complexity of the cascade of insulin signalling, several of the steps involved in the generation and propagation of the insulin signal can contribute to the molecular defect of insulin action. A reduced expression and a phosphorylation of the elements involved in the first steps of insulin signalling (IRS, PI3-kinase, PKB) have been found in tissue of type 2 diabetic patients, even if these alterations are primitive (genetic) rather than secondary to the alteration of metabolic milieu, this is still object of debate. The role of specific defects of these proteins has been established by knock-out animal models [21Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol, 2002, 57, 1-9.

Click here to see the Library]. For instance, IRS-1, IRS-2, and GLUT-4 knock-out mice have been shown to develop insulin resistance and glucose intolerance. However, it is when polygenic defect is created that an overt diabetes develops, leaving open the possibility that multiple defects are likely to contribute to the pathogenesis of insulin resistance and therefore of type 2 diabetes.

A role for the insulin signalling cascade has been recently demonstrated at the level of the ß-cell as well. ß-cell insulin receptor knock-out (ßIRKO) mice lose acute insulin response to glucose and they develop glucose intolerance [21Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol, 2002, 57, 1-9.

The antihyperglycemic effect of metformin is the result of the drug action on the insulin sensitivity on the liver, the muscle, and the adipose tissue. Though the effect on hepatic glucose production is considered preponderant, it is likely that it is the interaction among the effect on the three different tissues that bring about the overall beneficial effect of metformin.

Hepatic glucose production

Metformin exerts its antihyperglycemic effect mainly by inhibiting liver glucose output. Both gluconeogenesis and glycogenolysis are reduced by metformin, though the former seems to play a major role. By using nuclear magnetic resonance spectroscopy, Hundal et al. [23Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes, 2000, 49, 2063-9.

Click here to see the Library]determined the relative contribution of metformin effects on gluconeogenesis and glycogenolysis. In poorly controlled type 2 diabetic patients, metformin lowered the rate of glucose production through a reduction in gluconeogenesis (Fig 1). The inhibition of gluconeogenesis was associated with overall reduction in hepatic glucose production and 25-30% reduction of fasting plasma glucose. Similar findings have been reported by other investigators using different techniques [24Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab, 1996, 81, 4059-67.

Click here to see the Library]. There are several mechanisms that may account for this effect. In perfused liver, metformin decreases gluconeogenesis through inhibition of hepatic lactate uptake [27Radziuk J, Zhang Z, Wiernsperger N, Pye S. Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver. Diabetes, 1997, 46, 1406-13.

Click here to see the Library]. A potentiation effect of metformin on the suppressive action of insulin on gluconeogenesis also has received support by in vitro experiments [30Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin. Biochem Pharmacol, 1988, 37, 4353-8.

Click here to see the Library]. It is unclear whether metformin acts on mitochondrial respiration directly by slow permeation across the inner mitochondrial membrane or by unidentified cell-signalling pathways. In addition to the effect on gluconeogenesis, in vitro studies have indicated that metformin can reduce the overall rate of glycogenolysis [26Radziuk J, Bailey CJ, Wiernsperger NF, Yudkin JS. Metformin and its liver targets in the treatment of type 2 diabetes. Curr Drug Targets Immune Endocr Metabol Disord, 2003, 3, 151-69.

Click here to see the Library], while the result variability is the likely reflection of differences in the patients'characteristics (body weight, diabetes duration, severity of hyperglycaemia…) as well as in the dose of metformin (1-3 g/day) used in the studies. In placebo controlled studies, metformin has been shown to increase insulin-mediated glucose utilisation by 20-30% [35Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med, 2002, 137, 25-33.

Click here to see the Library]. The improvement of glucose utilisation (Fig 2)is almost completely due to non-oxidative glucose metabolism, a marker for glycogen synthesis (Fig 3), though in the fasting state it is glucose oxidation that increases after metformin treatment [36Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A. Glucose and lipid metabolism in non-insulin-dependent diabetes. Effect of metformin. Diabete Metab, 1991, 17, 180-4.

Click here to see the Library]. Consistent with these results are the findings obtained in diabetic rats [37Rossetti L, DeFronzo RA, Gherzi R, et al. Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism, 1990, 39, 425-35.

Click here to see the Library]. In these animals, the drug was able to normalise insulin-mediated glucose disposal and muscle glycogen synthesis. Therefore, in humans as well, the main post-receptor event of insulin action stimulated by metformin seems to be the glycogenic pathway.

Click here to see the Library]. These changes were not related to prevailing plasma insulin concentrations. The mechanism responsible for decreased FFA turnover is not completely understood, but it seems to be more likely related to increased re-esterification rather than decreased lipolysis [49Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes, 1994, 43, 920-8.

The reduction in the concentration and oxidation of plasma FFA can contribute to the improvement in insulin action that follows metformin treatment in obese type 2 diabetes. In these individuals, the common elevation in plasma FFA levels favours hepatic glucose production and peripheral insulin resistance [17Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest, 2002, 32 (suppl. 3), 14-23.

Click here to see the Library]. At the level of the liver, FFA excess induce the allosteric activation of the early steps of gluconeogenesis, while increased oxidation provides the required energy. In skeletal muscle, FFA can inhibit pyruvate dehydrogenase (Randle's cycle) but they can also impair glucose transport and/or phosphorylation [17Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest, 2002, 32 (suppl. 3), 14-23.

Click here to see the Library]. This aspect may become of even greater interest if one considers that insulin signalling ( i.e. insulin action) may be involved as well in the regulation of the secretory insulin function.

ß-cell

Though metformin is not considered to exert a significant effect on pancreatic ß-cells, isolated studies have claimed treatment to result in a potentiation of first-phase insulin secretion in response to glucose [56Althoff PH, Haupt E, Pichel C. Metformin increases insulin sensitivity and first-phase of the arginine-indiced insulin response in type 2 diabetes [Abstract]. Diabetes, 1991, 40 (suppl. 1), 342.

Biguanides and, therefore, metformin have been used for treating human disease for a very long time. The original active principle, guanidine, was initially extracted from Galega officinalis , a plant used in the Middle age to alleviate intense urination, to fight plague epidemics, to cure from snake bites, and to control the San Vito dance. Only, in the past decades, improvement of insulin resistance was included in this odd list of effects. In spite of the fact that metformin was the only available insulin sensitiser for a long time and still remains a main drug for improving insulin sensitivity, its intimate mechanism of action remains elusive.

Click here to see the Library]. Activation of AMPK by metformin was reported to be required for the decrease in glucose production and the increase in fatty acid oxidation in hepatocytes and for the increase in glucose uptake in skeletal muscle [62Zhou G, Myers R, Li Y, Chen Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest, 2001, 108, 1167-74.

Click here to see the Library]. AMPK, moreover, is involved, in gene regulation, by decreasing SREBP-1 mRNA (an insulin-stimulated transcription factor, implicated in pathogenesis of insulin resistance, dyslipidaemia and type 2 diabetes). Whether or not AMPK is the target of action of metformin or its activation is secondary to the generation of still unknown cell signals, remains to be established. Metformin activation of AMPK does not depend on depletion of cellular energy charge [64Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes, 2002, 51, 2420-5.

Click here to see the Library]. The effect of metformin is not as specific as rosiglitazone, a different insulin sensitiser, which also activates AMPK [65Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem, 2002, 277, 25226-32.

Click here to see the Library]. Interestingly enough, however, the mechanism of activation of metformin and rosiglitazone are distinct, so that the combination of the two could result in greater improvement of insulin sensitivity in insulin-resistant individuals. Therefore, some light has been shed on the molecular mechanism of action of metformin, though the precise target of the drug within the cell will require more investigation.

In summary, metformin represents an effective way to improve insulin resistance, active at all sites of impaired insulin action. At the level of the liver, metformin increases insulin-mediated suppression of hepatic glucose production, mainly by reducing gluconeogenesis. In skeletal muscle it promotes the insulin receptor phosphorylation, GLUT-4 translocation resulting in increased glucose uptake and glycogen synthesis. At the level of the adipose tissue it favours FFA re-esterification and inhibits lypolysis (Fig 4). Reduced levels of circulating FFA relieve lipotoxicity at the level of liver, skeletal muscle, and ?-cell. In this way, metformin indirectly increases insulin action and contributes to preserve ?-cell function. Thus, many of the metabolic alterations brought about by insulin resistance are improved by metformin, making the drug an ideal candidate for the treatment of type 2 diabetes and the metabolic syndrome [66Zimmet P, Collier G. Clinical efficacy of metformin against insulin resistance parameters: sinking the iceberg. Drugs, 1999, 58 (suppl. 1), 21-8.

Click here to see the Library]can account for the favourable effect on cardiovascular disease documented by the UKPDS [8UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998, 352, 854-65.

Click here to see the Library]. Since metformin is an insulin sensitizer, its action is fully operating in the presence of insulin resistance. As such, metformin is an antihyperglycaemic drug with very low risk for hypoglycaemia, therefore, making it a suitable tool for pharmacological prevention of type 2 diabetes [7Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346, 393-403.

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